J.P.Morgan Cazenove 17 juni 2019
FINCH-3 data further confirms strong profile for filgotinib. Focus shifts to post Phase III meeting with the regulators.
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Price: €108.80 14 Jun 2019
Over the weekend, we attended the European League Against Rheumatism (EULAR) annual congress in Madrid, Spain where the full data from the FINCH 3 trial was presented as a late breaking abstract in the late breaking abstracts session. In our view, as with the FINCH 1 data presentation, there were no surprises in the data, and so we believe the presentations of both studies further support our view that filgotinib has best in class safety profile with at least as strong efficacy compared to the rest of the JAK inhibitor class. The next key catalyst beyond EULAR for Galapagos is the communication of the outcome of the post Phase III meeting with the FDA, where we believe risk/ reward is fairly well balanced.
Efficacy profile of filgotinib was in line with that previously disclosed, speed of onset of response and remission also confirmed for filgotinib, which appears to be a class effect. Data for week 24 ACR20/50/70 responses were presented which were in line with that previously disclosed by Gilead/ Galapagos. The presenter noted that even though this was a methotrexate naïve population, it was actually a population with fairly high disease activity as even though the median duration of RA was 0.4 years, the average duration was around 2 years and around 30-40% of patients were being treated with corticosteroids. In addition, data was presented which demonstrated that filgotinib was superior to placebo on ACR20, ACR50 and ACR70 (200mg + MTX only) responses as early as week 2, confirming the fast onset of action of filgotinib, which appears to be a feature of the JAK inhibitor class. Remission (DAS-28-CRP <2.6) data was also presented at week 12 for filgotinib which looks comparable to the 15mg dose of upadacitinib in the SELECT-EARLY trial. Given the data presented, we continue to believe that the efficacy profile of filgotinib is just as good if not slightly better than the other JAK inhibitors on the market or in registration.
No new safety issues raised in the presentation, further confirming the best in class safety profile of filgotinib among the JAK inhibitors. Safety data presented for FINCH 3 was consistent with the Phase II DARWIN 3 study as well as the other trials in the Phase III FINCH programme (FINCH 1 and FINCH 2). No new safety signals were noted in the presentation. Rates of MACE and DVT/PE were very low (as previously disclosed in the GILD/ GLPG press release) and balanced with the methotrexate arm. Rates of infection were very low, and appear lower than the other JAK inhibitors in combination with MTX (filgotinib c.23/24% vs. Upa and Bari c.33-34%). In addition rates of opportunistic infection, serious infection and herpes zoster infection were also very low and appear lower with filgotinib compared to the other JAKs. Given this data, we believe that the best in class safety profile of filgotinib has been confirmed, at least as far out as 24 weeks. Beyond 24 weeks, the long term extension data from the DARWIN Phase II programme suggests a best in class safety profile (data presented out to 156 weeks), data from the FINCH 4 study (Long term extension study [up to 3 years] from FINCH 1-3) is expected to be presented in 2021, which we believe is likely to show consistent results with the DARWIN programme.
JAK inhibitor sessions highlighted the relationship between dose, selectivity and potentially adverse events. In a number of JAK inhibitor sessions and symposia we attended, first it was unanimous that JAK 1 is a key therapeutic target. That said, JAK 2 may also have some additional efficacy as it also blocks the cytokine GM-CSF, a validated target, but also hits the hemopeoetic system (blood and platelets) which may have an impact on adverse events, although some physicians were keen to express that this is not fully proven. On JAK selectivity, the KoLs described the fact that JAK inhibitors are not necessarily more selective for one type of JAK over the others, but it was highlighted that it is dose dependent i.e. at high enough doses all JAK inhibitors will hit all JAKs, it also depends on the particular JAK expression of the patient. From our discussions with Galapagos, filgotinib was tested up to a dose of 400mg without showing significant inhibition of either JAK 2 (possibly associated with DVT/PE) or JAK 3 (possibly associated with increased infection risk), which is comforting given that the highest dose for filgotinib in clinical trials is 200mg and we believe this could account for the strong safety profile. Other JAKs have seen issues in their trials/ development programme. The recent Xeljanz DVT/PE warning at a dose double the recommended dose on the label for RA could be indicative that Xeljanz (a JAK 1/3 inhibitor) has crossed its threshold to also target JAK 2 potentially leading to the increased DVT/PE risk – further data is required to confirm this. Baricitinib (JAK 1/2) showed increased DVT/PE at the 4mg dose, leading to the FDA only approving the 2mg dose (4mg dose is approved ex-US) and also for Upadacitinib (JAK 1), AbbVie have not filed the higher 30mg dose (only the 15mg dose filed with the FDA), and we suspect the 30mg dose could be close to the threshold where Upa could start to hit JAK 2 or JAK 3. Again, further clinical and mechanistic data is required to confirm these trends, however given the data we have seen so far we remain confident in the selectivity and safety profile of filgotinib.